# Mutational patterns and ancestry-linked profiles in a large hepatocellular carcinoma and combined hepatocellular–cholangiocarcinoma cohort

## TL;DR

This study analyzes genomic alterations in a large group of liver cancer patients, revealing patterns linked to sex and ancestry, and highlights the importance of genomic profiling for diagnosis and treatment.

## Contribution

The study presents the largest genomic analysis of HCC and cHCC–CCA patients, identifying ancestry- and sex-linked mutational profiles and actionable alterations.

## Key findings

- Female patients had lower frequencies of TERT, MYC, and CTNNB1 mutations but higher BAP1 mutations.
- East Asian patients showed increased TP53, MUTYH, and TET2 mutations and higher TMB-high tumors.
- cHCC–CCA had significantly higher rates of IDH1, IDH2, and FGFR2 alterations compared to HCC.

## Abstract

Despite significant therapeutic advancements, hepatocellular carcinoma (HCC) remains a highly fatal malignancy. To accelerate the development of targeted therapies, a comprehensive understanding of the spectrum of genomic alterations (GAs) is essential. Here, we present what is, to our knowledge, the largest genomic analysis of real-world HCC and combined HCC–cholangiocarcinoma (cHCC–CCA) patients.

Tumor samples from 2372 HCC patients and 150 patients with cHCC–CCA underwent genomic profiling using the FoundationOne® platform covering >290 genes, as well as tumor mutational burden (TMB) and microsatellite status.

Our comprehensive and representative analysis included 1793 male and 577 female patients across five genetic ancestries. Female patients exhibited lower frequencies of GAs in TERT, MYC, and CTNNB1, with higher rates of BAP1 GA. Patients of East Asian ancestry presented an increased frequency of TP53, MUTYH, and TET2 GAs, as well as a higher proportion of TMB-high tumors. Compared with HCC, cHCC–CCA exhibited higher frequencies of IDH1 (8.0% versus 0.3%), IDH2 (2.7% versus 0.04%), and FGFR2 (7.3% versus 0.3%) alterations. Potentially actionable alterations were detected in 19.5% of HCC patients and 34.7% of mixed histology. Histological re-assessment due to detection of GA uncommon for HCC was carried out in 117 patients, resulting in a change in diagnosis in 37 cases. Limitations include the absence of detailed clinical data and dependence on the CE-certified Foundation Medicine (FMI) platform for functional annotation of detected variants.

Our study represents one of the largest cohorts of HCC and cHCC–CCA patients with genomic data and highlights the critical role of integrated molecular diagnostics. Beyond uncovering therapeutic targets, next-generation sequencing profiling offers significant benefits in improving diagnostic accuracy for liver cancer.

•We present a granular analysis of GAs from clinical-grade sequencing of 2372 HCC and 150 HCC–CCA patients.•Mutational profiles vary based on sex and genetic ancestry.•Genomic profiling should be standard of care in HCC–CCA due to the high prevalence of actionable alterations.•Critical review of NGS results may lead to re-consideration of the original diagnosis.•Our study serves as a representative reference dataset for stratifying patients according to their GAs.

We present a granular analysis of GAs from clinical-grade sequencing of 2372 HCC and 150 HCC–CCA patients.

Mutational profiles vary based on sex and genetic ancestry.

Genomic profiling should be standard of care in HCC–CCA due to the high prevalence of actionable alterations.

Critical review of NGS results may lead to re-consideration of the original diagnosis.

Our study serves as a representative reference dataset for stratifying patients according to their GAs.